tbuckley/cabot-search huggingface dataset:
Identifying mechanisms of acquired immune escape from sequential, paired biopsies.
Authors: F. Stephen Hodi, David R. Spigel, Carlos E. De Andrea, Miguel F. Sanmamed, Elena Garralda, Josep Tabernero, Carlos A. Gomez-Roca, Bernadett Szabados, Thomas Powles, Russell Kent Pachynski, Lawrence Fong, Naiyer Rizvi, Shinkyo Yoon, Tae Won Kim, Do-Youn Oh, Alan Nicholas, Joy S. Tea, Alexander R. Abbas, Richard Price
Journal: Journal of Clinical Oncology (2022)

2519 Background: Resistance to immune checkpoint blockade (ICB) can manifest as disease progression either at the initiation of treatment (primary resistance) or after some initial response (acquired resistance). To better understand the mechanisms underlying acquired resistance, the imCORE Network is conducting a study (NCT03333655) to examine changes in tumor biology from pre-treatment to disease progression across cancer types. Methods: Eligible patients included those experiencing clinical benefit on ICB (defined as objective response or stable disease longer than 6 months) and had evaluable tissue samples from both pre-treatment and within 30 days of progression. Samples were subjected to whole exome sequencing (WES), RNA sequencing (RNA-Seq), and immunohistochemistry (IHC). Whole blood samples or adjacent normal tissue were used as a reference for tumor variant calling. Results: As of December 3 rd , 2021, 24 enrolled patients have complete sample pairs. Of those, melanoma, bladder, and lung were most common (n = 7, 6 and 5 pairs, respectively), but our cohort also included patients with breast cancer, squamous head &amp; neck, and renal cell carcinoma. IHC data unexpectedly showed a modest, but consistent increase in tumor infiltrating CD8+ T cells at progression. In addition, IHC evidence of a decrease in MHC-I proteins (HLA-A and B2M) suggest that in 5 out of 24 cases, key proteins needed for antigen presentation are lost. Global differential gene expression analysis showed that immune gene expression was significantly increased at progression, including numerous chemokines and significant enrichment in gene sets responsible for antigen presentation machinery. Protein-altering mutations at progression appeared in B2M in one patient, and CXCL9 in another. However, in most cases it is unclear what genetic alterations are responsible. We do not observe evidence of consistent IFNγ and Jak/stat signaling loss or antigen presentation loss. Conclusions: While ICB resistance is thought to be associated with a lack of immune response within the TME, we found that acquired resistance is usually associated with either maintenance or an increase in immune infiltration. Multiple alterations that are unique to individual patients also continue to emerge. Our data shows ICB resistance is multifactorial and associated with dynamic changes to markers amid immune activation and inhibition. Clinical trial information: NCT03333655.
A phase I study of TST001, a high affinity humanized anti-CLDN18.2 monoclonal antibody, in combination with capecitabine and oxaliplatin (CAPOX) as a first-line treatment of advanced G/GEJ cancer.
Authors: Jifang Gong, Ning Li, Weijian Guo, Jian Zhang, Hongli Li, Fuyou Zhao, Wei Li, Meili Sun, Zhenzhong Xia, Yu Shen, Jianming Wang, Lingmin Lu, Chuan Qi, Xueming Qian, Michael Shi, Lin Shen
Journal: Journal of Clinical Oncology (2022)

4062 Background: TST001 is a recombinant humanized IgG1 antibody specifically against human Claudin 18.2 (CLDN18.2) with high affinity and enhanced FcR engaging of NK cells, which can induce strong antibody-dependent cellular cytotoxicity (ADCC) activities. TST001 monotherapy dose-escalation study has been completed (IGCC2022-ABS-1152) and promising anti-tumor activities were observed in advanced gastric cancer patients with CLDN18.2 overexpression who had failed multiple lines of prior therapies. The current study is an open-label, multi-center, multiple cohorts, phase I clinical trial of TST001 monotherapy or in combination with standard treatments in Chinese patients with advanced or metastatic solid tumors (NCT04495296). Methods: This cohort is aimed to determine the recommended phase II dose, evaluate safety, tolerability and preliminary efficacy of TST001 in combination with CAPOX as a 1 st line treatment of advanced G/GEJ cancer. A 3+3 design was utilized in the dose escalation phase with treatment naïve advanced G/GEJ cancer patients regardless of Claudin18.2 expression. Claudin 18.2 positive G/GEJ cancer patients were planned to be enrolled in the dose expansion phase in selected dose cohorts. Results: The TST001/CAPOX combination cohort was initiated in August 2021 and is ongoing in multiple sites in China with a data cutoff date of January 27, 2022. 12 subjects were dosed with TST001 with a dose range from 1 to 8mg/kg Q3W in combination with the standard dose of CAPOX in the dose escalation phase and one subject with central lab tested Claudin 18.2 overexpression was dosed in the expansion phase of TST001 at 6mg/kg Q3W with CAPOX. There was no subject experienced dose-limiting toxicity. Treatment-emergent adverse events (TEAEs) were mostly grade 1-2, including nausea (76.9%), anemia (69.2%), vomiting, AST increased (63.8% respectively), hypoalbuminemia, ALT increased (46.2%, respectively). Treatment related grade 3 AEs were hypertension （15.4%）, anemia, hypoproteinemia, WBC count decreased, hypocalcemia aggravated (7.7%, respectively). Among the eight patients from the dose escalation part (with no CLDN18.2 expression selection yet with measurable disease ) with at least one post-treatment tumor assessment, four had achieved partial response, three had achieved stable disease and one had progressive disease as the best tumor response per RECIST1.1. Conclusions: Conclusion: TST001 in combination with CAPOX in first line gastric cancer patients is safe and encouraging anti-tumor activities have been observed. Additional data from the 6 mg/kg dose expansion cohort will be updated at the meeting. Clinical trial information: NCT04495296.
Mass cytometry reveals a conserved immune trajectory of recovery in hospitalized COVID-19 patients
Authors: Cassandra E. Burnett, Trine Line Hauge Okholm, Iliana Tenvooren, Diana M. Marquez, Stanley Tamaki, Priscila Munoz Sandoval, Andrew Willmore, Ravi Patel, Yumiko Abe-Jones, Saurabh Asthana, Alexander Beagle, Sharvari Bhide, Cathy Cai, Maria Calvo, Sidney A. Carrillo, Suzanna Chak, Zachary Collins, Spyros Darmanis, Gabriela K. Fragiadakis, Rajani Ghale, Jeremy Giberson, Pat Glenn, Ana Gonzalez, Kamir Hiam-Galvez, Alejandra Jauregui, Serena Ke, Tasha Lea, Deanna Lee, Raphael Lota, Leonard Lupin-Jimenez, Viet Nguyen, Nishita Nigam, Logan Pierce, Priya Prasad, Arjun Rao, Sadeed Rashid, Nicklaus Rodriguez, Bushra Samad, Cole Shaw, Austin Sigman, Pratik Sinha, Kevin Tang, Luz Torres Altamirano, Erden Tumurbaatar, Vaibhav Upadhyay, Alyssa Ward, Kristine Wong, Chun Jimmie Ye, Kimberly Yee, Mingyue Zhou, Carolyn M. Hendrickson, Kirsten N. Kangelaris, Charles R. Langelier, Matthew F. Krummel, Prescott G. Woodruff, Carolyn S. Calfee, David J. Erle, K. Mark Ansel, Matthew H. Spitzer
Journal: Immunity (2022)
Optimizing the fellow oncology continuity clinic: Factors associated with a meaningful experience.
Authors: Carl Shultz, Wajeeha Rizvi, Salah Ud Din Safi, Maria Hafez, Jean Gabriel Bustamante Alvarez, Nour Daboul, Amir Kamran
Journal: Journal of Clinical Oncology (2022)

e23012 Background: Fellowship programs use a variety of continuity clinic models including general, disease/system specific, or both. The longitudinal timing also varies from 6-months, 1-year, or the entirety of fellowship. At WVU, we use a 6-month disease specific model where fellows rotate with a specific attending. Given the increasing complexity of care for patients with oncologic diagnoses, we sought to establish a general continuity clinic within an academic cancer institute to model the skills needed to effectively transition to independent practice. Additionally, we proposed to identify key elements that make for a meaningful continuity clinic experience. Methods: We created a 42 question, anonymous online survey comparing general clinic to the disease specific clinic and administered it to our current 2nd and 3rd year fellows. Independent variables were Likert-scale ratings (1=strongly disagree, 2= disagree, 3=neutral, 4=agree, 5=strongly agree) on four main themes: patient characteristics, clinic operations, preceptor characteristics, and educational value. Results: Seven out of seven fellows responded. The majority of them answered that 1 new patient and 4 return patients were “just right” per half day of general clinic, while 1-2 new patients and 5 or more return patients were “just right” per half day of disease specific clinic. Within the general clinic, the number of patients with lung, GU, and GI oncology was noted as “just right” while breast and other (e.g., CNS, head and neck, sarcoma) were identified as “too few”. Table shows a sample of questions asked and differences among the two clinics. The most evident disparity was autonomy of patients. A weekly, multispecialty planning session was also rated highest in terms of educational value for general clinic. Conclusions: We demonstrated a general continuity clinic can be successfully implemented within an academic cancer center. While there are pros and cons to both types, several key characteristics to a meaningful continuity clinic experience were identified including: adequate ratio of new and return patients, wide variety of diagnoses, increased autonomy and ownership of patients, consistent preceptor and support staff, and weekly planning session for increased preparation and educational value.[Table: see text]
Health and healthcare equity in the cancer care sector in Canada: Results of a rapid scoping review.
Authors: Leah Lambert, Tara C Horrill, Michael R. McKenzie, Annette Browne, Kelli Stajduhar, Jagbir Kaur, Shannon Cheng, Amber Bourgeois, Fuchsia Howard, Scott Beck, Sally Thorne
Journal: Journal of Clinical Oncology (2022)

e18536 Background: Despite advances in research and treatment, and a publicly funded healthcare system in Canada, alarming inequities exist across the cancer continuum. Although attention to these inequities is increasing, it is unclear how organizations are acting upon calls to address health equity. Our objective was to identify how health and healthcare equity are being discussed as a goal or aim within the Canadian cancer care sector. Methods: A rapid scoping review was conducted for published and unpublished literature on health equity in the Canadian cancer care sector. As this review was part of a larger initiative aimed at informing policy recommendations and research priorities with specific time constraints, we also drew on the WHO’s guidance for conduct of rapid reviews to strengthen health policy and systems. Five biomedical databases, 30 public health and multidisciplinary websites and databases, and Google were searched. Documents available in English, published between 2008 and 2021, and that discussed health or healthcare equity in the Canadian cancer context were included. Results: Of 3,678 documents screened, 83 were included for full text analysis. The focus on health equity within the Canadian cancer care sector increased 3-fold between 2015-2021 when compared with the period 2008-2014. Only 25% of documents included a definition of health equity. Concepts such as inequity, inequality, and disparity were frequently used interchangeably or in a tokenistic way, resulting in conceptual muddling. Less than half of documents included an explicit health equity goal. Stated health equity goals ranged from broad to specific, with examples from across the cancer continuum. A range of actions were described to address equity goals, including health system improvements and policy and planning considerations. Most actions were framed as recommendations rather than actions taken or underway, and few documents described measurement of progress toward health equity goals. Conclusions: Health equity is a growing priority in the cancer care sector, however conceptual clarity is needed to guide the development of robust equity goals, specific objectives, and meaningful action. Moreover, evaluation mechanisms to understand the impacts of actions on equity goals are urgently needed. If we are to advance health equity in the cancer care sector, a coordinated and integrated approach will be required to enact transformative and meaningful change.
Shock
Authors: Dan Roche
Journal: JAMA (2022)

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TBIO-01. Mutation Profiling of Paediatric Solid Tumours in a Cohort of South African Patients
Authors: Lindiwe Lamola, Erin Manolas, Amanda Krause
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The incidence of childhood cancer incidence is increasing gradually in low-middle income countries, such as South Africa. Globally, there is an extensive range of familial- and hereditary-cancer syndromes, where underlying germline variants increase the likelihood of developing cancer in childhood. Next-Generation Sequencing (NGS) technologies have been key in determining the occurrence and genetic contribution of germline variants to paediatric cancer development. We aimed to design and evaluate a candidate gene panel, specific to inherited cancer-predisposing genes to provide a comprehensive insight into the contribution of germline variants to childhood cancer. METHODS: 32 paediatric patients (aged 0-18 years) diagnosed with a malignant tumour were recruited and biological samples were obtained. After quality control, DNA was sequenced using an ion Ampliseq 50 candidate gene panel design and Ion Torrent S5 technologies. Sequencing variants were called using Ion Torrent Suite software and were subsequently annotated using Ion Reporter and Ensembl's VEP. High priority variants were manually analysed using tools such as MutationTaster, SIFT-INDEL and VarSome. Putative identified candidates were validated via Sanger Sequencing. RESULTS: The patients studied had a variety of cancers, the most common being nephroblastoma (13), followed by osteosarcoma (4) and astrocytoma (3). We identified 10 pathogenic / likely pathogenic variants in 10 patients, most of which were novel. CONCLUSIONS: According to literature, we expected ~10% of our patient population to harbour pathogenic or likely pathogenic germline variants, however we reported about 3 times (~30%) more than we expected. Majority of the identified variants are novel; this may be because this is the first study of its kind in an understudied South African population
Immunotherapy and chemo-immunotherapy for non–small cell lung cancer with novel actionable oncogenic driver alterations.
Authors: Laura Mazzeo, Teresa Beninato, Chiara Carlotta Pircher, Marta Brambilla, Sara Manglaviti, Alessandro De Toma, Giulia Galli, Arsela Prelaj, Roberto Ferrara, Claudia Proto, Giuseppe Lo Russo, Monica Ganzinelli, Marina Chiara Garassino, Paolo Marchetti, Filippo G. De Braud, Mario Occhipinti
Journal: Journal of Clinical Oncology (2022)

9057 Background: Immune checkpoint inhibitors (IO) single agent or in combination with platinum chemotherapy (CT-IO) are standard of care for Stage IV non-small cell lung cancer (NSCLC) according to PD-L1 expression. While the efficacy of IO among patients (pts) with common EGFR and ALK alterations appears to be limited, its activity in pts with novel oncogenic drivers alterations is not well characterized. Compared to non-oncogene-addicted NSCLC, the overall response rate (ORR) seems to be similar in BRAF and c-MET altered NSCLC, lower in RET altered NSCLC, while data are less consistent in HER2 and EGFR exon 20 (EGFRex20) altered NSCLCs. Methods: From January 2016 to January 2022, we retrospectively enrolled pts with Stage IV NSCLC that received IO or combination CT– IO in any line, ECOG PS 0 - 2 and detection of MET exon 14 skipping mutations (METex14), BRAF mutations (V600E or non-V600E), RET rearrangement, HER2 point mutations (HER2mut)/exon 20 insertions (HER2ex20) or uncommon EGFR mutations (uEGFRmut)/EGFRex20. A review of clinicopathologic and molecular features and an analysis of response to combination or single-agent IO were conducted. Results: Among sixty-four pts enrolled, 20 (31%) had METex14, 19 (30%) had EGFR alterations [12 (19%) EGFRex20, 7 (11%) uEGFRmut], 8 (12%) had BRAF mutation (3 V600E and 5 non-V600E), 13(20%) had HER2 alterations [7 (11%) HER2ex20, 6 (10%) HER2mut] and 4 (6%) were RET rearranged. 43 received IO single agent and 21 received CT-IO. With a median follow up of 22 months (m), median progression free survival (mPFS) was 5.40 m (0.95 CI 4.73-6.9) overall, 6.77m in CT-IO arm (0.95 CI 5.37-NA) and 5.10m in IO arm (0.95 CI 2.60-6.7), with a trend to better mPFS for CT-IO (p 0.054). Regarding specific mutations irrespectively from treatment arm, NSCLC harboring METex14 showed a mPFS of 5.33 m (0.95 CI, 2.30-13.9), BRAF 9.9 m (0.95 CI, 6.70-NA), EGFR 4.93 m (0.95 CI, 1.80-6.9), HER2 11.4 (0.95 CI, 4.2-NA), RET 5.28 (0.95 CI, 1.42-NA). Disease control rate (DCR) was better in the CT-IO arm vs IO one in the overall population (84.2% vs 50%, p 0.013). Conclusions: Novel driver alterations seem to show a benefit from IO treatments. CT-IO seems to have a better outcome in terms of DCR. Therefore, IO-based treatment should be evaluated also in tumors harboring novel driver alterations. [Table: see text]
Improving supportive care for patients with thoracic cancer.
Authors: Lakedia Charman Banks, Kris Kapphahn, Millie Das, Debra Wujcik, Carrie Tompkins Stricker, Lucinda Shanbhag, Stephanie Lin, Ge Zhu, Manali I. Patel
Journal: Journal of Clinical Oncology (2022)

1520 Background: Improving lung cancer care among Veterans is a priority within the Veterans Affairs due to higher rates of lung cancer incidence, morbidity, and mortality among Veterans compared to non-veterans. Unaddressed symptom burden is common due to many factors including complex comorbidities, psychosocial challenges, smoking history and limited social support networks. Additionally, complications from social determinants of health can obstruct successful discussions of symptom-burden between Veterans and their clinical care teams which can limit compliance with recommended symptom management strategies. To overcome these barriers, we conducted a randomized controlled trial to test the effectiveness of a lay volunteer-led proactive symptom assessment and symptom intervention. The objective was to determine if the intervention improved clinician documentation from baseline to 6-months post-enrollment compared to usual care. Secondary outcomes included change in patient activation, health-related quality of life (HrQOL), and symptom-burden. Methods: Patients were randomized into the lay volunteer proactive symptom assessment intervention plus usual cancer care (intervention group) or usual cancer care alone (control group). We conducted electronic health record review to assess primary cancer-clinician symptom documentation of Veterans’ symptoms identified as moderate-to-severe at baseline and 6-months using the Edmonton Symptom Assessment Scale. Patient surveys with validated assessments were used to assess patient activation, HrQOL and symptom burden at baseline (time of enrollment) and 6-months post-enrollment. We used regression models to evaluate differences in our primary and secondary outcomes. Results: 60 Veterans were consented and randomized into the study (29 control; 31 intervention). There were no differences in demographic or clinical factors across groups. The median age was 70 years (range 56-85), 95% were male, 70% identified their race as White, 53% were married and 48% had a 2-year or 4-year college degree. The majority had at least 3 comorbidities (54%), diagnosed with stage 3 or 4 (62%) and received systemic treatment with chemotherapy and/or radiation (77%). At 6-months post-enrollment as compared to baseline, the intervention group had greater improvements in symptom documentation (56% from 12.5% vs. 29% from 43%, p = 0.01), greater improvements in patient activation (p&lt;0.001), HrQOL (&lt;0.001), and lower symptom burden (p&lt;0.001) than the control group. Conclusions: Integration of proactive symptom assessment by lay volunteers has a significant and meaningful effect on symptom documentation, patient activation, quality of life, and reducing symptom burden among Veterans with lung cancer. Clinical trial information: NCT03216109.